(300 WORDS MAX.) Alzheimer's and other tauopathies are medical problems growing to historical proportions that threaten the long term viability of medical care systems world-wide. The number of Americans living with Alzheimer's disease is growing fast. Alzheimer's costs today are 1.2% of the US GDP. However, effective disease-modifying treatments have yet to be developed. Very few researches have been developed to target tau. Our prior work has determined Tubastatin A, a highly selective HDAC6 inhibitor, was effective in lowering tau and improving the behavioral phenotype of the Tg4510 mouse model of amyloid deposition. SW-100 was identified recently with a higher affinity, slightly longer half-life and substantially increased brain permeability than Tubastatin A. The proposed project will focus on SW-100 together with its four analogs in in vitro and in vivo efficacy studies, ADMET, and Tg4510 mouse studies. Success in this project will provide further validation of this therapeutic approach and lay a strong foundation for moving such NCEs to the clinic.